The systemic toxicity of chemotherapy is a widely recognized problem in oncology. Off-target damage often persists indefinitely, adversely affects patient survival and compliance, and severely restricts dose and treatment options. Drug side effects remain a significant limitation for administration because of both expected and unexpected effects. Novel anticancer therapies have drastically improved life expectancy for numerous patients; however, persistent toxicity for long-term cancer survivors has become an issue, particularly for pediatric patients. In particular, cardiac toxicity may offset the increase in life expectancy resulting from the therapy due to mortality from cardiac problems including heart failure, myocardial ischemia, arrhythmias, hypertension, and thromboembolism.
Three common drugs used to treat cancers include doxorubicin (DOX), epirubicin (EPI), and cisplatin (FIG. 1), all of which act on DNA. DOX and EPI function by intercalating between DNA base pairs, while cisplatin is a DNA crosslinker that functions by binding to guanine. A major problem for these anticancer compounds is toxicity in non-targeted tissues. DOX and EPI toxicity can result in cardiomyopathy and congestive heart failure. Similarly, cisplatin exhibits side effects including extensive nephrotoxicity and neurotoxicity. Cumulative dosage of DOX is generally limited by clinicians to 400-450 mg/m2, though lower cumulative dosages (300 mg/m2) are known to increase the risk of congestive heart failure. Still, a single standard dose of DOX (50-75 mg) can result in severe side effects, while higher dosages of DOX are known to be associated with greater tumor suppression. Consequently, a balance must be struck in order to maximize the dose, leading to better tumor suppression, while simultaneously avoiding catastrophic off-target toxicity.
Limiting a patient's lifetime cumulative dose is the most effective way to avoid cardiotoxicity, but this approach necessarily limits anti-cancer efficacy.
The present invention(s) is intended to address some of these deficiencies.